Hypertension. 2001;37:744-748
(Hypertension. 2001;37:744.)
© 2001 American Heart Association, Inc.
Workshop: Endothelial Cell Dysfunction Leading to Diabetic Nephropathy
Focus on Nitric Oxide
Michael S. Goligorsky;
Jun Chen;
Sergey Brodsky
From the Departments of Medicine, Physiology, and Biophysics, and the
Program on Biomedical Engineering, State University of New York, Stony Brook.
Correspondence to M. Goligorsky, Division of Nephrology and Hypertension, SUNY, Stony Brook, NY 11794-8152. E-mail mgoligorsky{at}mail.som.sunysb.edu
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Abstract
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Clinical
manifestations of diabetic nephropathy are an expression
of
diabetic microangiopathy. This review revisits the previously
proposed
Steno hypothesis and advances our hypothesis that
development of
endothelial cell dysfunction represents a
common
pathophysiological pathway of diabetic
complications. Specifically,
the ability of glucose to scavenge nitric
oxide is proposed
as the initiation phase of
endothelial dysfunction. Gradual
accumulation of
advanced glycated end products and induction
of
plasminogen activator inhibitor-1,
resulting in the decreased
expression of endothelial
nitric oxide synthase and reduced
generation of nitric oxide, are
proposed to be pathophysiologically
critical
for the maintenance phase of endothelial
dysfunction.
The proposed conceptual shift toward the role of
endothelial
dysfunction in diabetic complications may
provide new strategies
for their prevention.
Key Words: nitric oxide synthase collagen plasminogen diabetes mellitus
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Introduction
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Type 2 diabetes
mellitus has reached epidemic proportions,
and one of its ominous
complications, diabetic nephropathy,
represents
today the leading cause of end-stage renal
failure.
1 2
Clinical manifestations of diabetic nephropathy include
microalbuminuria, heralding incipient
nephropathy, followed
by albuminuria or
nephrotic-range proteinuria, elevated blood
pressure, development of
glomerulosclerosis,
tubulointerstitial
fibrosis, and relentless decline
in glomerular filtration
rate.
1 2 3 4
The most characteristic prognostic feature in this group
of patients is
the high risk of cardiovascular complications,
much
more so than in diabetics without nephropathy. Several
important mediators of diabetic nephropathy have been
proposed,
such as transforming growth factor-ß, accumulation
of the
extracellular matrix, reactive oxygen intermediates,
and protein kinase
C, to name a few, and have been comprehensively
reviewed.
1 2 3 4
However, the pathophysiological origin of
clinical
presentations of diabetic nephropathy can be
traced
back to microvasculopathy and macrovasculopathy
(Figure 1
),
and the focus of this review will be on the
mechanisms for
development and maintenance of
endothelial cell dysfunction
in diabetic
nephropathy.

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Figure 1. Clinical manifestations of diabetic nephropathy and potential role of ECD, defined as dysregulation of eNOS/NO availability, in pathophysiology of these clinical presentations. BP indicates blood pressure; GFR, glomerular filtration rate.
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In 1988, Torsten Deckert delivered a Claude Bernard Lecture
in which the Steno hypothesis, a unifying proposal that
albuminuria of diabetic nephropathy is a sign
of the global vascular dysfunction, was
introduced.5 Because only
less than one third of patients with type I diabetes mellitus tend to
develop renal disease, it was speculated that a genetic predisposition,
supposedly at the level of
N-deacetylase (a key enzyme
responsible for the sulfation of heparan sulfate proteoglycans) gene
polymorphism, contributes to the loss of the anionic charge barrier
of endothelial cells and basement membranes, resulting
in a widespread rise in vascular permeability and vasculopathy. The
hypothesis to be developed below takes stock of the above broad view
that albuminuria is an indicator of a systemic
microvascular lesion in diabetes mellitus and revises the Steno
hypothesis to advance a hypothesis on the developmental mechanisms of
endothelial cell dysfunction in diabetes.
 |
The Concept of Endothelial Cell
Dysfunction
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The last 20 years have brought about a lucid
realization that
the vascular endothelium is not a mere
barrier between intravascular
and interstitial
compartments. In fact, the vascular endothelium
has
received the status of an organ, albeit a widely spread
one, which is
responsible for the regulation of the hemodynamics,
angiogenic vascular remodeling, and metabolic, synthetic,
inflammatory,
antithrombogenic, and prothrombogenic processes. As any
other
organ, the vascular endothelium is a subject for
dysregulation,
dysfunction, insufficiency, and failure. This latter
category
has become the basis for the recently coined syndrome of
endothelial
cell dysfunction (ECD). This syndrome,
initially introduced
to describe defective
endothelium-dependent vasorelaxation
in patients at
risk for development of atherosclerosis even
before
angiographic or ultrasonographic evidence of the disease
becomes
detectable
6 7 8
(reviewed in Reference 9 and
10
9 10 ),
9 10 has been
broadened to encompass disturbances in
the barrier function of
the vascular endothelium; its impaired
antithrombogenic
properties; perturbed angiogenic capacity;
inappropriate regulation of
vascular smooth muscle tonicity,
proliferative capacity, and migratory
properties; perturbed
synthetic functions; and deterrent of neutrophils
and monocytes
from diapedesis. The pathophysiology of
endothelial cells characterized
by these abnormalities,
expressed at various degrees, is emerging
as a hallmark of several
highly prevalent cardiovascular and
renal diseases,
including diabetes mellitus, as well as their
complications.
Although several markers of ECD have been proposed (elevated
circulating levels of von Willebrand factor,
plasminogen activator inhibitor
[PAI]-1, some adhesion molecules, isoprostane, and thrombomodulin
[reviewed in Reference
1111 ]),11
endothelium-dependent vasorelaxation has remained the
gold standard in assessing endothelial function and
dysfunction.12 The
demonstration of a paradoxical vasoconstriction in atherosclerotic
coronary arteries in response to infusion of acetylcholine, a
clinical equivalent of Furchgotts and
Zawadzkis13 observation of
endothelium-dependent vasorelaxation and its reversal
in denuded vessels, pointed to the pivotal role of
endothelial nitric oxide synthase (eNOS) in the
pathogenesis of ECD. Indeed, accumulated evidence suggests that many of
the above-mentioned aspects of ECD are intimately linked to the
expression and function of this enzyme. In particular, nitric oxide
(NO) generation inhibits platelet aggregation; similarly, adhesion
of leukocytes to the vascular endothelium is inhibited
by
NO.14 15 16 17 18 19 20
Endothelial regulation of vascular smooth muscle
relaxation, proliferation, and migration is in part governed by the
integrity of the
L-arginineeNOSNO
system.21 22 23
In addition, vascular/endothelial permeability and some
synthetic functions of endothelial cells have been
linked to the activity of eNOS (reviewed in Reference 1111 ). Hence, NO
production or availability can regulate diverse functions in
endothelial cells per se and their interaction with
circulating formed elements (both inflammatory and thrombogenic
interactions) and vascular smooth muscle cells. In fact, recent
findings from Casellass laboratory (Bouriquet et
al24 ) demonstrated that in
the absence of hyperlipidemia, inhibition of eNOS alone
is sufficient to induce the deposition of Sudan blackpositive lipid
droplets in arcuate and interlobular renal but not in afferent
arterioles, resulting in increased vascular wall thickness. This is an
important demonstration of the role of NO generation in atherosclerotic
damage to the medium-size renal arteries.
The main thesis of this review, therefore, is that the
pathophysiological basis for the Steno hypothesis
is endothelial cell dysfunction and, specifically, the
dysfunction of the eNOS/NO system. Below, we shall consider two phases
of its development: the initiation phase and the maintenance
phase.
 |
Initiation Phase of
Endothelial Cell Dysfunction
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What triggers ECD in diabetes mellitus? Numerous
epidemiological
and pathophysiological studies
point to the importance of hyperglycemia
in development of
macrovascular and microvascular
complications.
25
One of the early alterations observed in diabetes mellitus
that may lead to initiation of endothelial cell
dysfunction is the decreased bioavailability of NO. In a series of
studies performed in collaboration with S. Gross (Weill Medical
College), we have demonstrated that
supraphysiological concentrations of
D-glucose (30 mmol/L) are
capable of scavenging NO.26
Specifically, we demonstrated that acute exposure of human
endothelial cells to glucose, at levels found in plasma
of diabetic patients, results in a significant blunting of NO responses
to the eNOS agonists bradykinin and A23187. Monitoring of NO generation
by purified recombinant bovine eNOS in vitro, with the use of
amperometric electrochemical detection and an NO-selective porphyrinic
microelectrode, showed that glucose causes a progressive and
concentration-dependent attenuation of detectable NO. Addition of
glucose to pure NO solutions similarly elicited a sharp decrease in NO
concentration, indicating that glucose promotes NO loss. Electrospray
ionization tandem mass spectrometry, using negative ion monitoring,
directly demonstrated the occurrence of a covalent reaction involving
unitary addition of NO (or a derived species) to glucose. This effect
of glucose may account for the acute hypertensive response to
hyperglycemia,27 28
as well as for multiple cellular effects, as detailed in
Table 1. In addition, extrapolating from these in
vitro data, each episode of hyperglycemia, as transient as it might be,
will lead to the temporary decrease in the bioavailability of NO and
the reversible impairment of NO-dependent functions of the
endothelium, as illustrated in
Figure 2. It should be emphasized that glucose-NO adducts
formed are unstable and gradually release bioactive NO, but this
messenger molecule will be then delivered to inappropriate targets at
the wrong time. The proposed consequences of hyperglycemic episodes, at
the level of the vascular endothelium, are summarized
in
Figure 3, which illustrates the transient decline in NO
bioavailability and transient proatherogenic changes in the vascular
wall. Another major consequence of the elevated plasma glucose levels,
which, however, shows poor reversibility and in fact has a cumulative
dependence on hyperglycemia, is the formation of advanced glycation
end-products (AGEs)
(Figure 4).

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Figure 2. Relevant targets of NO and the consequences of NO deficiency. uPA indicates urokinase type plasminogen activator; MMPs, matrix metalloproteinases; bFGF, basic fibroblast growth factor; TGF, transforming growth factor; BMPs, bone morphogenic proteins; and CTGF, connective tissue growth factor.
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Transition From Initiation to
Maintenance Phase of Endothelial
Dysfunction
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Several arguments exist that link the formation of AGEs
to
the maintenance phase of endothelial cell
dysfunction. Previous
studies by Bucala et
al
29 showed that AGEs have
an NO-scavenging
effect. AGEs are considered among the leading causes
of diabetic
complications, especially in the development of
atherosclerotic
vascular disease (see References 30
30 to 34 and
references
therein).
30 31 32 33 34
Their mode of action is linked to
changes in physicochemical properties
of matrix proteins such
as collagen-to-collagen cross-linking and
tissue rigidity,
leading to decreased solubility and susceptibility of
proteins
to enzymatic digestion. In fact, infusion of AGEs to
nondiabetic
animals can reproduce many vascular complications of
diabetes.
Recent data have demonstrated that AGEs consume
endothelium-derived
NO, thus compromising vasodilatory
responses and diminishing
antiproliferative action of
NO.
29 Indeed, substantial
literature
exists on the stimulation of NOS in diabetic animals and
humans,
whereas the biological effects of NO are deficient (reviewed
in
References 35
35 to
38).
35 36 37 38
These findings of
NO quenching by AGEs may explain the observed
deficiency of
angiogenic responses, which require basal NO
production, at
sites of interstitial fibrosis. In
addition, this functional
NO deficiency may complement other factors in
stimulating the
proliferation of fibroblasts and the accumulation of
the extracellular
matrix, both of which are important contributors to
the progression
of diabetic nephropathy (reviewed in
Reference 39
39 ).
39
Collectively,
these findings provide the conceptual basis to link AGEs
with
the development of the maintenance phase of
endothelial cell
dysfunction. We shall present our
data, further confirming
and developing these
observations.
 |
Maintenance Phase of
Endothelial Cell Dysfunction
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Endothelial cells cultured in 3D
glycated collagen I gels showed
delayed capillary cord branching,
examined with a previously
described in vitro angiogenesis
assay.
40 This branching
incompetence
was chronologically associated with the induction of
several
genes, as detected by a differential display approach
(Table
2
). One of such genes was PAI-1, a well-established
marker
of endothelial dysfunction in several
pathological conditions,
including diabetes mellitus. Studies that used
exogenous PAI-1
or neutralizing antibodies to PAI-1 have demonstrated
that
it is critically involved in the observed delay in capillary
cord
branching in
vitro.
41
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Table 2. Polymerase Chain ReactionSelected Subtraction
Search for Differentially Displayed cDNA Clones in Human Umbilical Vein
Endothelial Cells Exposed to Glycated Collagen I
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To confirm the role of PAI-1 in vivo, angiogenesis assays
were performed in PAI-1-/- mice. Aortic explants obtained from
these mice42 43
showed uninhibited vascular sprouting in 3D cultures in glycated
collagen or matrigel, as opposed to the vessels obtained from wild-type
mice. Furthermore, aortic explants obtained from streptozotocin-induced
diabetic (STZ) mice or rats, although indistinguishable from control
animals 4 weeks after STZ injection, showed defective capillary
sprouting by 8 weeks. Interestingly, when STZ diabetes was modeled in
PAI-1-/- mice, explanted aortic cultures showed a much improved
angiogenic capacity compared with wild-type animals (S. Brodsky,
unpublished observations). Collectively, these data demonstrate that
PAI-1 is an early-response gene induced in endothelial
cells presented with glycated collagen and that the product
of this gene is causally involved in the impaired angiogenic
competence. Together with the existing clinical studies incriminating
PAI-1 in diabetic
complications,11 44 45
it is conceivable that PAI-1 is an important contributor to the
maintenance of endothelial cell dysfunction.
The question is: Does PAI-1 affect the eNOS/NO system?
Recent studies (S. Brodsky, unpublished observations)
demonstrated that treatment of cultured human umbilical vein
endothelial cells with the constitutively active PAI-1
resulted in the reversible decrease of immunodetectable eNOS. This was
associated with the reduced ability of endothelial
cells to generate NO in response to bradykinin or A23187. The similar
phenomenon was observed in endothelial cells cultured
on the surface of glycated collagen or matrigel. This series of
observations strongly suggests that the maintenance phase of
endothelial cell dysfunction in diabetes mellitus could
be attributed not only to the scavenging of NO by elevated glucose or
AGEs but to the chronic suppression of its expression and function by
the activated PAI-1.
Assuming the latter takes place in vivo, the state of
chronic endothelial NO deficiency will have a broad
range of functional alterations, as schematically shown in
Figure 5. Specifically, eNOS/NO deficiency should lead to
the impaired balance between the matrix deposition and degradation,
result in activation of transforming growth factor-ß and connective
tissue growth factor, promote proatherosclerotic changes in the
vascular wall, accelerate formation of AGEs, impair angiogenic
remodeling of the vascular bed to the ischemic tissues, and
interfere with insulin secretion and glucose utilization by skeletal
muscles (both processes NO-dependent). All these sequels of eNOS/NO
deficiency have clear-cut relevance to the progression of diabetic
nephropathy.
Conclusions
The hypothesis presented herein ascribes
clinical manifestations and their respective
pathophysiological mechanisms to the development of
endothelial cell dysfunction. The trigger for its
development is hyperglycemia per se, but the maintenance phase
is tightly linked to the accumulation of AGEs. The pivotal function of
endothelial cells perturbed during the initiation and
maintenance phases is eNOS/NO production or
availability. We propose that the initiation event(s) is linked to
glucose scavenging of NO during transient episodes of hyperglycemia. At
the maintenance phase, however, eNOS expression and function
may be perturbed chronically, thus leading to the persistent
dysfunction of the vascular endothelium. This
hypothesis, while stemming from the Steno hypothesis on
endothelial pathology preceding diabetic complications,
puts forward eNOS/NO dysfunction as the critical variable
responsible for the initiation and maintenance of
endothelial dysfunction. Shifting the emphasis from
N-deacetylase to the eNOS/NO
system may have important implications for therapy of diabetic
complications, including diabetic
nephropathy.
 |
Acknowledgments
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These studies were supported in part
by National Institutes
of Health grants DK-45462, DK-52783, and
DK-54602.
Received October 27, 2000;
first decision November 27, 2000;
accepted December 11, 2000.
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Diabetes,
June 1, 2006;
55(6):
1651 - 1659.
[Abstract]
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A. Mezentsev, R. M. H. Merks, E. O'Riordan, J. Chen, N. Mendelev, M. S. Goligorsky, and S. V. Brodsky
Endothelial microparticles affect angiogenesis in vitro: role of oxidative stress
Am J Physiol Heart Circ Physiol,
September 1, 2005;
289(3):
H1106 - H1114.
[Abstract]
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C. S. Wilcox and D. Gutterman
Focus on oxidative stress in the cardiovascular and renal systems
Am J Physiol Heart Circ Physiol,
January 1, 2005;
288(1):
H3 - H6.
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R. D. Moraes, G. Gioseffi, A. C. L. Nobrega, and E. Tibirica
Effects of exercise training on the vascular reactivity of the whole kidney circulation in rabbits
J Appl Physiol,
August 1, 2004;
97(2):
683 - 688.
[Abstract]
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S. V. Brodsky, F. Zhang, A. Nasjletti, and M. S. Goligorsky
Endothelium-derived microparticles impair endothelial function in vitro
Am J Physiol Heart Circ Physiol,
May 1, 2004;
286(5):
H1910 - H1915.
[Abstract]
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S. Clement, S. S. Braithwaite, M. F. Magee, A. Ahmann, E. P. Smith, R. G. Schafer, and I. B. Hirsch
Management of Diabetes and Hyperglycemia in Hospitals
Diabetes Care,
February 1, 2004;
27(2):
553 - 591.
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F. Locatelli, B. Canaud, K.-U. Eckardt, P. Stenvinkel, C. Wanner, and C. Zoccali
The importance of diabetic nephropathy in current nephrological practice
Nephrol. Dial. Transplant.,
September 1, 2003;
18(9):
1716 - 1725.
[Abstract]
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L. H. Opie and H.-H. Parving
Diabetic Nephropathy: Can Renoprotection Be Extrapolated to Cardiovascular Protection?
Circulation,
August 6, 2002;
106(6):
643 - 645.
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B.-S. Kim, J. Chen, T. Weinstein, E. Noiri, and M. S. Goligorsky
VEGF Expression in Hypoxia and Hyperglycemia: Reciprocal Effect on Branching Angiogenesis in Epithelial-Endothelial Co-Cultures
J. Am. Soc. Nephrol.,
August 1, 2002;
13(8):
2027 - 2036.
[Abstract]
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M. S. Segal, A. Bihorac, and M. Koc
Circulating endothelial cells: tea leaves for renal disease
Am J Physiol Renal Physiol,
July 1, 2002;
283(1):
F11 - F19.
[Abstract]
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